1. Field of the Invention
This invention relates to devices and methods for the noninvasive determination of concentrations of hemoglobin and hematocrit in a human subject in vivo, particularly for the noninvasive determination of concentrations of hemoglobin and hematocrit in a human subject in vivo, where the temperature of a defined subcutaneous volume of a body part of the subject is controlled and varied between preset boundaries.
2. Discussion of the art
Non-invasive (hereinafter xe2x80x9cNIxe2x80x9d) monitoring of analytes in the human body by optical devices and methods is an important tool in clinical diagnostics. NI monitoring techniques, which do not require obtaining a sample from the human body or inserting any instrumentation into the human body, have several advantages, including, but not limited to, ease of performing tests, reduction of pain and discomfort to the patient, and decreased exposure to potential biohazards.
The most established non-invasive optical technique is pulse oximetry. Oxygenation of blood in tissue and cerebral oxygen saturation can be measured, and the measurement can be used for clinical applications. See Jobsis, xe2x80x9cNon-invasive, Infrared Monitoring of Cerebral and Myocardial Oxygen Sufficiency and Circulatory Parametersxe2x80x9d, Science, 198, 1264-67 (1977), and Shiga, et al., xe2x80x9cStudy of an Algorithm Based on Model Experiments and Diffusion Theory for a Portable Tissue Oximeterxe2x80x9d, J. Biomed. Optics; 2(2), 154-161 (1997).
Hemoglobin is the protein that transports oxygen. The hematocrit value provides an indication of the hemodynamics of the body. Non-invasive determination of the hemoglobin concentration (Hb) and the hematocrit value (Hct), when available, can be useful in blood donation centers, intensive care units, and surgical operation rooms. Non-invasive determination of the hemoglobin concentration and the hematocrit value can potentially be applied for diagnosis of anemia in infants and mothers, for localizing tumors, and for diagnosis of hematoma and internal bleeding. See S. Gopinath, et al., xe2x80x9cNear-infrared spectroscopic localization of intracamerial hematomasxe2x80x9d, J. Neurosurgery, 79, 43-47 (1993).
Concentration of hemoglobin and the ratio of oxygenated hemoglobin to total hemoglobin in blood are important parameters for indicating the anemic state and wellness of a patient. Hemoglobin is a protein having a molecular weight of 64,500 daltons; thus, 1 gram of hemoglobin is equivalent to 1.55xc3x9710xe2x88x925 mole. The concentration of hemoglobin is expressed in g/dL. The hematocrit value is the ratio of volume of red blood cells to total blood volume, which comprises the volume of red blood cells and the volume of plasma. The hematocrit value is expressed as a percentage (i.e., volume percentage of red cells in whole blood). While measurement of concentration of hemoglobin provides an indication of the oxygen transport status of the patient, measurement of the hematocrit value provides an indication of concentration of both red blood cells for transport of oxygen and plasma for transport of nutrients. The measurement of the hematocrit value is particularly important when a change in body hemodynamics is expected, such as during operations of long duration, such as, for example, vascular and orthopedic surgery. Other applications of hematocrit measurement include the treatment of hemorrhage in accident victims and the monitoring of cancer patients undergoing chemotherapy. Yet another application of hematocrit measurement involves monitoring kidney dialysis patients to reduce the potential for incomplete dialysis or excessive dialysis of the patient. Incomplete dialysis leaves toxins behind. Excessive dialysis leads to shock.
The standard method currently used for measuring hematocrit value is an invasive method. Typically, a blood sample is obtained from a patient or a donor and centrifuged in a capillary tube to separate red blood cells from plasma. The length of the column in the capillary tube containing red blood cells and the total length of the column in the capillary tube containing both the red blood cells and the plasma are measured, and the ratio of these lengths is the hematocrit value (Hct). Other methods for determining the hematocrit value involve the use of a flow cytometer, where a known volume of blood is injected in a fluid stream and the number of red blood cells (RBC) and their mean volume is determined. The total volume of RBC is calculated and the hematocrit value is determined from the volume of the sample and the total RBC volume. Hemoglobin concentrations can be determined in vitro by a photometric method, where a blood sample is hemolyzed and the heme moiety is released from hemoglobin at a high pH condition. The absorption of this heme moiety is determined at wavelengths of 577 nm and 633 nm.
U.S. Pat. No. 5,227,181, U.S. Pat. No. 5,553,615, and U.S. Pat. No. 5,499,627 describe hematocrit monitoring devices that involve the use of light of a limited number of wavelengths. These patents do not involve a non-invasive measurement or an apparatus having a means for controlling the temperature of a sample. Because the spectral and optical properties of samples of human tissue depend on temperature in the near infrared region of the electromagnetic spectrum, hematocrit and blood oxygenation measurements in this region of the electromagnetic spectrum can be inaccurate, when temperature is not controlled. Zhang et al., xe2x80x9cInvestigation of Non-invasive in Vivo Blood Hematocrit Measurement Using NIR Reflectance Spectroscopy and Partial Least-Squares Regressionxe2x80x9d, Applied Spectroscopy, vol. 54, no. 2, 294-299 (2000), discloses a method for non-invasively determining the hematocrit value in vivo during cardiac bypass surgery by employing a large number of wavelengths in the near-infrared region of the electromagnetic spectrum. Temperature of the patient was found to change during surgery. A high number of wavelengths and a partial least squares regression analysis were used in an effort to minimize the effect of temperature on the hematocrit value during the determination. Although the device and method described by Zhang et al. provide good calibration and prediction for a given patient during surgery, establishing a model to predict the hematocrit values across more than one patient was less successful. Systematic bias between patients was observed.
The effect of temperature on the scattering and absorption properties of tissue has been of interest in the art of non-invasive monitoring. Thermal effects of laser excitation, photocoagulation, and temperature effect on skin optics have been described in the art. See, for example, W-C. Lin et al., xe2x80x9cDynamics of tissue reflectance and transmittance during laser irradiationxe2x80x9d, SPIE Proceedings, 2134A Laser-Tissue Interaction V, 296-303 (1994); and W-C. Lin, xe2x80x9cDynamics of tissue optics during laser heating of turbid mediaxe2x80x9d, Applied Optics, Vol. 35, No. 19, 3413-3420 (1996). Other publications include J. Lauferet al., xe2x80x9cEffect of temperature on the optical properties of ex vivo human dermis and subdermisxe2x80x9d, Phys. Med. Biol. 43 (1998) 2479-2489; and J. T. Bruulsema et al., xe2x80x9cOptical Properties of Phantoms and Tissue Measured in vivo from 0.9-1.3 xcexcm using Spatially Resolved Diffuse Reflectancexe2x80x9d, SPIE Proceedings 2979, 325-334 (1997).
U.S. Pat. Nos. 3,628,525; 4,259,963; 4,432,365; 4,890,619; 4,926,867; 5,131,391; and European Patent Application EP 0472216 describe oximetry probes having heating elements designed to be placed against a body part. U.S. Pat. No. 5,148,082 describes a method for increasing the blood flow in a patient""s tissue during a photoplethysmography measurement by heating the tissue with a semiconductor device mounted in a sensor. U.S. Pat. No. 5,551,422 describes a glucose sensor that is brought to a specified temperature, preferably somewhat above normal body-temperature, with a thermostatically controlled heating system.
U.S. application Ser. No. 09/080,470, filed May 18, 1998, assigned to the assignee of this application, and WO 99/59464 describe a non-invasive glucose sensor employing a means for controlling the temperature of a sample. One purpose of controlling the temperature of a sample is to minimize the effect of physiological variables. U.S. application Ser. No. 09/098,049, filed Nov. 23, 1998, assigned to the assignee of this application, and U.S. application Ser. No. 09/419,461, filed Oct. 15, 1999, assigned to the assignee of this application, disclose the use of an optical element that is brought in contact with skin, the temperature of which skin is being controlled.
Although a variety of detection techniques have been disclosed in the art, there is still no commercially available device that provides hemoglobin and hematocrit measurements non-invasively with an accuracy that is comparable to measurements made by current commercially available invasive methods. Non-invasive measurements obtained by prior art methods are based on the assumption that the tissue comprises a single uniform layer that has a single uniform temperature. As a result, current approaches to non-invasive metabolite testing, such as hemoglobin determination or hematocrit monitoring, have not achieved acceptable precision and accuracy.
Thus, there is a need for improved apparatus and methods for non-invasive metabolite testing. It is desired that these methods and devices not be adversely affected by variations in skin temperatures and that they account for the effects of the various layers of skin. It is also desired that these methods and devices account for the effect of temperature on the optical properties of the various layers of skin.
This invention provides a method for the determination of hemoglobin and hematocrit by means of an apparatus that is capable of controlling the temperature of a defined subcutaneous volume of human skin. The method involves a calculation of hemoglobin concentration and hematocrit value that takes into consideration the values of optical parameters of the sample at various pre-set temperatures. The apparatus and method employ steady state optical measurements of samples, such as, for example, human tissue, by means of a reflectance tissue photometer and localized control of the temperature of the sample.
According to the method of this invention, an optical signal from a defined subcutaneous volume of human skin is measured as the temperature of this volume is controlled. The method and apparatus of this invention allow determination of hemoglobin concentration and hematocrit value non-invasively in a population of subjects having different skin colors by means of steady state reflectance measurements. The method of this invention for determination of hemoglobin concentration and hematocrit value is useful for monitoring patients, testing at the point of care, and screening for anemia. In contrast to other attempts in the prior art that rely on signals of cardiac pulses, the method of this invention has the advantage for the determination of analytes in weak cardiac pulse situations, such as, for example, in elderly patients.
In one aspect, this invention provides an improved method for the non-invasive determination of hemoglobin concentration or hematocrit value in a sample. The method comprises the steps of:
(a) setting the temperature of an area of skin of a body part to a first temperature, the first temperature being below the core temperature of the body,
(b) performing an optical measurement in which at least one light introduction site on the surface of the skin is illuminated by a light beam at at least one wavelength and the light re-emitted from the underlying dermal layers is collected at at least one light collection site, the distance(s) between the at least one light introduction site and the at least one light collection site being selected to restrict the sampling depth of the body part to within the epidermis and dermis layer, the temperature being maintained at a constant value during the optical measurement,
(c) setting the temperature of the area of skin of the body part to at least a second temperature that is within the physiological temperature range,
(d) repeating step (b) at the at least second temperature,
(e) determining a plurality of optical parameters at each temperature and determining the dependence of at least one of the aforementioned optical parameters on temperature,
(f) establishing a calibration relationship that relates (1) at least one of the plurality of optical parameters at a given temperature and (2) the dependence of at least one of the plurality of optical parameters on temperature with the concentration of hemoglobin or the hematocrit value measured independently, and
(g) determining the concentration of hemoglobin or the hematocrit value by means of a subsequent determination of the plurality of optical parameters at a given temperature and the dependence of the at least one of the aforementioned optical parameters on temperature and the calibration relationship established in step (f).
The temperatures at which the area of the skin is maintained during the measurements lie within the physiological temperature range, namely, 10xc2x0 C. to 45xc2x0 C. Preferably, temperatures are selected so as to assure comfort during the measurements. Accordingly, a preferred temperature range is 15xc2x0 C. to 42xc2x0 C., and a more preferred temperature range is 20xc2x0 C. to 40xc2x0 C.
The light used in the method of this invention can have a wavelength ranging from about 400 nm to about 1900 nm. It is possible to select a range of wavelengths that allows the use of one type of detector. Thus, a wavelength range of from about 400 nm to about 1100 nm can be used with a silicon detector, and a wavelength range of from about 700 nm to about 1900 nm can be used with an Indium/gallium arsenide detector. Hybrid detectors having wider wavelength ranges can be used to cover light having wavelengths in all or most of the visible and near infrared regions of the electromagnetic spectrum.
Spatially resolved diffuse reflectance measurement techniques can be used to perform the optical measurements of the method of this invention. The distance between the at least one light introduction site and the at least one light collection site preferably ranges from about 0.1 mm to about 10 mm, in order to allow collection of light re-emitted from the epidermis and dermis layers only and to minimize contributions from adipose tissue and muscle tissue. The use of small separation distances also allows for better control of the temperature of the tissue layer during the measurement.
Another method of performing the measurements of this invention is the selectable distance method, described in U.S. application Ser. No. 09/366,084, filed Aug. 3, 1999, incorporated herein by reference.
The volume of tissue subjected to temperature control and optical examination ranges from about 0.1 cubic millimeter to about 10 cubic millimeters, preferably from about 0.2 cubic millimeter to about 5 cubic millimeters, and more preferably from about 0.2 cubic millimeter to about 2 cubic millimeters.
Statistical methods for establishing a correlation between the optical signal obtained non-invasively and the measurement of hemoglobin concentration or hematocrit value determined invasively in order to establish a calibration relationship include, but are not limited to, linear least squares, partial least squares, and principal component analysis.
Another embodiment of the invention is an improved method for the determination of hemoglobin and hematocrit in human body that comprises:
(a) setting the temperature of an area of skin of a body part to a given temperature, the given temperature being below the core temperature of the body,
(b) performing an optical measurement in which at least one light introduction site on the surface of the skin is illuminated by a light beam at at least one wavelength and the light re-emitted from the underlying dermal layers is collected at at least one light collection site, the distance(s) between the at least one light introduction site and the at least one light collection site being selected to restrict the sampling depth of the body part to within the epidermis and dermis layer, the given temperature being maintained at a constant value during the optical measurement, whereby the optical measurement generates a measurable signal,
(c) correlating the measurable signal of step (b) with hemoglobin concentration or hematocrit value determined by an independent method to establish a calibration relationship, and
(d) determining the concentration of hemoglobin or the hematocrit value from a signal from a subsequent optical measurement and the calibration relationship of step (c).
This invention provides several advantages over the prior art. The measurement method does not rely on the cardiac pulse, and thus is more suitable for the elderly and for individuals having poor peripheral circulation. Improvement in the measurement of the concentration of hemoglobin and the hematocrit value is brought about by changing light penetration depth in a defined volume of tissue and by sampling blood vessels deeper in the skin, without the need to exert pressure or raise temperature to alter flow of blood. In one embodiment, the method involves measurement of a defined volume of the dermis layer of the tissue at a constant temperature below the body core temperature, thereby avoiding the effects of temperature fluctuation on the data. This embodiment allows improved correlation with venous hemoglobin concentration and hematocrit values, even though simple instrumentation is employed.